A morpholino nucleic acid monomer whose base moiety is guanine (hereinafter referred to as a “G monomer”) has an oxygen atom bound to the carbon atom in the 6-position of the guanine. Accordingly, when a morpholino nucleic acid oligomer is synthesized using a G monomer whose hydroxy group in the 6-position of the guanine is not protected, a side reaction occurs. For example, in a condensation process, the hydroxy group in the 6-position of the guanine may react with the activated site of other morpholino nucleic acid monomer to form a phosphorylated form, which may then react with ammonia used in a deprotection process, resulting in a conversion from the guanine to a diaminopurine. Such a side reaction serves as a substantial cause of a reduction in the synthesis yield of an intended substance.
For the purpose of suppressing the aforementioned side reaction, AVI BioPharma Inc. reported a G monomer whose hydroxy group in the 6-position of the guanine is protected by a pivaloyloxybenxyl group (POB group) (for example, see WO2009/064471 A1). Nevertheless, the POB group is converted during the deprotection process into 4-methylenecyclohexa-2,5-dienone, which is added to an NH moiety of the morpholine in the morpholino nucleic acid oligomer to form a by-product.
In addition, WO2009/064471 A1 includes a description of other protecting groups for the hydroxy group in the 6-position of the guanine. Such other protecting groups disclosed in WO2009/064471 A1 include, for example, 4-nitrophenethyl, phenylsulfonylethyl and methylsulfonylethyl. These protecting groups, however, undergo conversion during the deprotection process to reactive species such as 4-nitrostyrene, which is added to an NH moiety of the morpholine in the morpholino nucleic acid oligomer to form a by-product. While a silyl-type protecting group such as t-butyldimethylsilyl is also known, it has been reported to undergo a side reaction similar to that of the G monomer whose hydroxy group in the 6-position of the guanine is not protected, since it is not stable and tends to be cleaved easily under a morpholino nucleic acid oligomer synthesis condition. Furthermore, a phenyl ether-type protecting group and a carbamate-type protecting group are also known, but it is reported about these protecting groups that a detachment of the protecting group is imperfect in the deprotection process or that condensation efficiency turns worse in the condensation process.